BMPR-II deficiency elicits pro-proliferative and anti-apoptotic responses through the activation of TGFβ-TAK1-MAPK pathways in PAH

Md Talat Nasim, Takeshi Ogo, Hasnin M Chowdhury, Lan Zhao, Chien-nien Chen, Christopher Rhodes, Richard C Trembath

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57 Citations (Scopus)

Abstract

Pulmonary arterial hypertension (PAH) is a cardiovascular disorder associated with enhanced proliferation and suppressed apoptosis of pulmonary arterial smooth muscle cells (PASMCs). Heterozygous mutations in the type II receptor for bone morphogenetic protein (BMPR2) underlie the majority of the inherited and familial forms of PAH. The transforming growth factor β (TGFβ) pathway is activated in both human and experimental models of PAH. However, how these factors exert pro-proliferative and anti-apoptotic responses in PAH remains unclear. Using mouse primary PASMCs derived from knock-in mice, we demonstrated that BMPR-II dysfunction promotes the activation of small mothers against decapentaplegia-independent mitogen-activated protein kinase (MAPK) pathways via TGFβ-associated kinase 1 (TAK1), resulting in a pro-proliferative and anti-apoptotic response. Inhibition of the TAK1-MAPK axis rescues abnormal proliferation and apoptosis in these cells. In both hypoxia and monocrotaline-induced PAH rat models, which display reduced levels of bmpr2 transcripts, this study further indicates that the TGFβ-MAPK axis is activated in lungs following elevation of both expression and phosphorylation of the TAK1 protein. In ex vivo cell-based assays, TAK1 inhibits BMP-responsive reporter activity and interacts with BMPR-II receptor. In the presence of pathogenic BMPR2 mutations observed in PAH patients, this interaction is greatly reduced. Taken together, these data suggest dysfunctional BMPR-II responsiveness intensifies TGFβ-TAK1-MAPK signalling and thus alters the ratio of apoptosis to proliferation. This axis may be a potential therapeutic target in PAH.

Original languageEnglish
Pages (from-to)2548-58
Number of pages11
JournalHuman Molecular Genetics
Volume21
Issue number11
DOIs
Publication statusPublished - 1 Jun 2012

Keywords

  • Animals
  • Apoptosis
  • Bone Morphogenetic Protein Receptors, Type II
  • Cell Proliferation
  • Cells, Cultured
  • Familial Primary Pulmonary Hypertension
  • Hypertension, Pulmonary
  • MAP Kinase Kinase Kinases
  • Mice
  • Pulmonary Artery
  • Rats
  • Signal Transduction
  • Transforming Growth Factor beta

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